Ovarian cancer is the fifth most common cause of cancer death in females and the most lethal gynecologic cancer. Globally, an estimated 240,000 people are diagnosed with ovarian cancer each year, with 22,530 new cases in the United States in 2019. Parity, oral contraceptive use, and lactation are protective, while early menarche, late menopause, and nulliparity have opposite effects. The “incessant ovulation” theory has thus emerged, in which a higher number of ovulations may be a cause of epithelial ovarian cancer (EOC). However, the mechanisms of this theory are unknown; one possibility is that the chance of acquiring a cancer-initiating pathogenic variant increases with each ovulatory cycle because of a microenvironment that promotes DNA damage. In this dissertation, we aimed to leverage genetic epidemiologic data to test this potential mechanism by evaluating the presence of gene-environment interaction between DNA repair capacity (measured through the presence of pathogenic variants in DNA repair genes) and lifetime ovulatory years (LOY). In the first aim of this dissertation, we conducted a systematic review and meta-analysis, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to formally evaluate the strength of evidence and to generate summary point estimates for the association between LOY and EOC. We then executed two analytic aims to evaluate if the presence of pathogenic variants in DNA repair genes exacerbated the increase in ovarian cancer risk associated with LOY. In Aim 2, we evaluated interaction on the additive scale in the United Kingdom (UK) Biobank through use of a novel DNA repair capacity score developed in this dissertation, measured by quantifying the number of pathogenic variants present per individual from a list of 163 DNA repair genes, using whole exome sequencing (WES) data. In Aim 3, we evaluated the presence of interaction between pathogenic BRCA1/2 status and LOY in the Breast Cancer Family Registry (BCFR), a cohort enriched for familial risk. In both empirical aims, we assessed the presence of interaction on the additive scale using the relative excess risk due to interaction (RERI) formula. We compared results across the two empirical aims. We found the relationship between lifetime ovulations and ovarian cancer risk to be consistent and replicable in the published literature. In pooled estimates from 22 published studies, a one-year increase in LOYs was associated with a 4% (3-6%) increased risk of ovarian cancer and those with a high number of ovulations (compared to low LOYs) had a 2.15-fold (95% CI 1.82, 2.54) increased risk of ovarian cancer. We also confirmed the positive association between increasing LOYs and ovarian cancer risk in the UK Biobank and the BCFR cohorts. Although interaction on the additive scale was not detected, there were strong positive associations between pathogenic variants in DNA repair genes and ovarian cancer risk. In the UK Biobank, the presence of at least one pathogenic variant in a DNA repair gene was associated with a significant 27% increased risk of epithelial ovarian cancer (EOC) (95% CI 5-55%). Among women at high risk of ovarian cancer due to family history of breast and/or ovarian cancer, there was a strong relationship between BRCA1/2 pathogenic variants and ovarian cancer, regardless of the number of ovulations experienced. The association between LOY and ovarian cancer was found to be consistent and replicable, despite differences in study design, covariates, and measurement. We also detected robust evidence that increasing lifetime ovulations and pathogenic DNA repair variants were associated with ovarian cancer risk. Such variants were exceedingly rare in both cohorts, which limited power to detect interaction in an already rare cancer. Despite such associations, there was no evidence of synergy between LOY and impaired DNA repair capacity, but rather, high LOY and impaired DNA repair capacity may be independent risk factors of ovarian cancer. Each exposure may describe a separate class of women at increased risk of ovarian cancer that should be targeted for future prevention and screening strategies.

<p>This research addresses low dose ionizing radiation exposure and risk. While it is well understood that high doses of radiation lead to deleterious health effects, there is controversy surrounding the definitive level of risk associated with exposure to low doses of radiation. These types of low level exposures are relevant to patients undergoing medical imaging procedures. This thesis considers the health effects associated with nuclear medicine, specifically positron emission tomography (PET), with the radiopharmaceutical 2-deoxy-2-(¹⁸F)fluoro-D-glucose(¹⁸F-FDG). These effects were studied in mice to eliminate the high degree of variability among human patients.</p> <p>The early response to various injection activities of ¹⁸F-FDG was first considered in terms of the DNA damage response in the haematopoietic cells of wild-type <em>Trp53+/+</em> mice. The late effects of PET scans with clinically relevant doses of ¹⁸F-FDG, such as carcinogenesis, were evaluated in cancer prone <em>Trp53+/-</em> mice. The role of p53 in the response to low dose radiation was also investigated to explore how short term responses correlate with p53-mediated cancer risk. This work has helped to advance the understanding of low dose radiation biology and the health risks associated with medical imaging procedures.</p> / Doctor of Philosophy (PhD)

Yes / Objective The hypothesis that sleeve gastrectomy (SG) is not associated with an increase in mucosal colorectal cancer (CRC) biomarkers, unlike Roux-en-Y gastric bypass (RYGB), was tested. Design and Methods Rectal mucosa, blood, and urine were obtained from morbidly obese patients (n = 23) before and after (median 28 months) SG, as well as from nonobese controls (n = 20). Rectal epithelial cell mitosis and apoptosis, crypt size/fission, and pro-inflammatory gene expression were measured, as well as systemic inflammatory biomarkers, including C-reactive protein (CRP). Results The mean pre-operative body mass index in SG patients was 65.7 kg/m2 (24.7 kg/m2 in controls). Mean excess weight loss post-SG was 38.2%. There was a significant increase in mitosis frequency, crypt size, and crypt fission (all P < 0.01) in SG patients versus controls, as well as evidence of a chronic inflammatory state (raised CRP and mononuclear cell p65 NFκB binding), but there was no significant change in these biomarkers after SG, except CRP reduction. Macrophage migration inhibitory factor mRNA levels were increased by 39% post-SG (P = 0.038). Conclusions Mucosal biomarkers of CRC risk do not increase at 6 months following SG, unlike RYGB. Biomarkers of rectal crypt proliferation and systemic inflammation are increased in morbidly obese patients compared with controls.

No description available.

Inhalation risks on human health for hazardous air pollutants emitted from MACT I petroleum refining industry were determined using EPA HEM-3 Program. Methodology included compiling vertical and fugitive emissions from 2002 National Emissions Inventory for sources inside two facilities in Louisiana, 'Motiva Norco' and 'Valero St. Charles' refineries. Six cases were modeled applying EPA criteria, where cancer risks are 'low' if the probability is. 1/1, 000, 000, and non-cancer risks are harmful when hazard quotient is > 1. It was demonstrated that fugitive emissions have more impact on human health than the verticals because of their significant portion of the total refining emissions. HAPs can cause moderate adverse effects in humans living nearby refineries, as 113 people resulted in high risk of respiratory problems with Valero emissions, 4571 people resulted in 'moderate' risk of getting cancer with Motiva emissions, 2702 people with Valero emissions, and 11, 282 people with both refineries' emissions.

The BEIR V preferred relative risk models and standard life-table techniques are used to project lifetime fatal cancer risk factors for average members of the Canadian population. Uncertainties associated with projections are evaluated for: (1) sampling variation (statistical error), (2) extrapolation of risks to low doses and low dose rates, (3) projection of excess lifetime cancer risks beyond the current periods of human observation in epidemiological studies, (4) the transfer of site-specific excess risk coefficients between populations with differing baseline cancer rates, and (5) the effect of differences in the age and sex distributions among occupations in the Canadian "radiation" workforce. Results are used to assess the applicability of the fatal cancer risk estimates recommended in ICRP publication 60 to the Canadian population. It was found that sampling variation, extrapolating to low doses and dose rates, projecting excess risks beyond current periods of observation, and the uncertainty in how to transfer site-specific excess risks between populations all cause substantial variations in lifetime cancer risk projections. Site-specific cancer risk projections may be expected to vary by factors of 2 to 5, depending on the source of uncertainty. Site-specific differences were found in the fatal cancer risk factors projected for "average" male and female workers among different occupations in the Canadian workforce. Site-specific worker averages differed by as much as a factor 3. Female average risk factors for digestive cancers were substantially higher than male workers, while male average risk factors tended to be higher for leukemia and respiratory cancer. Overall however, the majority of worker risk factors were within 2.5% of the site-specific projections for the workforce as a whole. The ICRP-60 nominal fatal cancer risk estimates, tissue weighting factors, and lifetime risk projections for prolonged radiation exposure were all in good agreement with equivalent values derived in this report for the Canadian population. In view of the uncertainties, the results suggest the ICRP estimated cancer risks are as good as any presently available and supports the use of the ICRP recommended values for the planning and regulation of radiation protection in Canada. / Thesis / Master of Science (MS)

The purpose of this thesis is to explore differences in lifetime excess cancer risk (LECR) for Canadians from intake of contaminants in food and beverages based on geographic location, gender and income levels. A probabilistic risk assessment approach (Monte Carlo simulation) was used to estimate the range and frequency of possible daily contaminant intakes for Canadians, and associate these intake levels with lifetime excess cancer risk. Monte Carlo risk simulation was applied to estimate probable contaminant intake and associated lifetime excess cancer risk from arsenic, benzene, lead, polychlorinated biphenyls (PCBs) and tetrachloroethylene (PERC) in 60 whole foods from the dietary patterns of 34,944 Canadians from 10 provinces, as derived from Health Canada’s Canadian Community Health Survey, Cycle 2.2, Nutrition (2004)1. These results were compared to the current Health Canada guideline that suggests that 10 extra cancers per one million people is a negligible risk. Of the 5 contaminants tested in my model arsenic showed the greatest difference between urban and rural estimated lifetime excess cancer risk, although extra cancers in both rural and urban Canada were predicted from exposure to PCB and benzene. Lifetime excess cancer risk is estimated to be higher for men in Canada for all five contaminants, with an emphasis on males in British Columbia compared to females from the dietary intake of arsenic. When based on income level, my model predicts extra cancers higher for low and middle incomes from dietary exposures to arsenic, benzene, lead and PERC, however, high income populations are more likely to have extra cancers from dietary intake of PCBs. / Graduate

published_or_final_version / Diagnostic Radiology / Master / Master of Philosophy

Formaldehyde is one of the most prevalent and toxic chemicals found indoors, where we spend ~90% of our lives. Chronic exposure to formaldehyde indoors, therefore, is of particular concern, especially for sensitive populations like children and infants. Unfortunately, no effective filtration control strategy exists for its removal. While research has shown that proteins in sheep's wool bind permanently to formaldehyde, the extent of wool's formaldehyde removal efficiency and effective removal capacity when applied in active filtration settings is unknown. In this research, wool capacity experiments were designed using a plug flow reactor and air cleaner unit to explore the capacity of wool to remove formaldehyde given different active filtration designs. Using the measured wool capacity, filter life and annual costs were modeled in a typical 50 m₃ room for a variety of theoretical filter operation lengths, air exchange rates, and source concentrations. For each case, annual filtration costs were compared to the monetary benefits derived from wool resale and from the reduction in cancer rates for different population types using the DALYs human exposure metric. Wool filtration was observed to drop formaldehyde concentrations between 60-80%, although the effective wool removal capacity was highly dependent on the fluid mechanics of the filtration unit. The air cleaner setup yielded approximately six times greater capacity than the small-scale PFR designed to mimic active filtration (670 [mu]g versus 110 [mu]g HCHO removed per g of wool, respectively). The outcomes of these experiments suggest that kinematic variations resulting from different wool packing densities, air flow rates, and degree of mixing in the units influence the filtration efficiency and effective capacity of wool. The results of the cost--benefit analysis show that for the higher wool capacity conditions, cost-effectiveness is achieved by the majority of room cases when sensitive populations like children and infants are present. However, for the average population scenarios, filtration was rarely worthwhile, showing that adults benefit less from reductions in chronic formaldehyde exposure. These results suggest that implementation of active filtration would be the most beneficial and cost-effective in settings like schools, nurseries, and hospitals that have a high percentage of sensitive populations. / text

Breast cancer incidence, particularly late-stage disease, is increasing in U.S. women under 40 years of age, pointing to the importance of exposures acting early in the life course to increase breast cancer risk. Earlier onset of breast development has recently been identified as an independent risk factor for breast cancer. Thus, identifying modifiable factors that can delay the onset of breast development may provide an opportunity for breast cancer primary prevention starting early in life. This dissertation examined the influence of the early-life environment on the age at onset of breast development through: 1) a systematic review of the literature relating maternal pre-pregnancy body size, gestational weight gain (GWG), birth size, and infant growth to the timing of breast development and menarche; 2) analyses assessing the associations between these factors and the onset of breast development in a pubertal cohort enriched for breast cancer family history (BCFH); and 3) a pilot study assessing whether these factors are associated with serum levels of insulin-like growth factor(IGF)-1 and insulin-like growth factor binding protein(IGFBP)-3 during puberty. Our systematic review identified 96 studies, the majority of which examined the association between birthweight and age at menarche. Although low birthweight is often cited as a risk factor for early menarche, the majority of studies (40/73 total) that examined this association did not observe a statistically significant association. Differences in exposure assessment, inadequate control for confounders, and differences in postnatal growth across studies may drive inconsistencies in the birthweight literature. In contrast, higher maternal body mass index (BMI) prior to pregnancy, GWG in excess of recommended guidelines and faster rates of weight gain between birth and 2 years of age were consistently associated with earlier age at breast development and menarche. We used data from the LEGACY Girls Study, a prospective cohort of girls primarily ages 6-13 years at baseline in which approximately 50% of girls had a family history of breast cancer, to examine the relations between maternal factors, birth size and infant growth and the onset of breast development, defined as a maternal report of breast Tanner stage 2 or greater. Daughters of women with a pre-pregnancy BMI of 25 or greater and who gained 30lbs or more during pregnancy experienced breast development at an earlier age than daughters of women with a pre-pregnancy BMI less than 25 and who gained less than 30lbs. This association was similar in girls with and without a BCFH. Birthweight and birthlength were not associated with the timing of breast development. In a subset of LEGACY girls with height and weight data during infancy available from medical records, we examined the associations between changes in weight-for-age and length-for-age Z-scores from birth to 1 year of age and the onset of breast development. We observed a modest association between faster rates of weight gain from 0-12 months and earlier age at breast development. When we examined smaller age intervals within infancy, faster weight gain from 2-4 months and 6-9 months were each associated with an earlier age at breast development. A similar pattern was observed for growth in length, and these associations did not vary by BCFH. In our pilot study including 109 girls with available serum samples between 6-17 years of age at the LEGACY New York site, rapid weight gain from 0-12 months was associated with higher mean levels of IGF-1 relative to IGFBP-3. Although not statistically significant, girls with a maternal pre-pregnancy BMI≥25 and GWG≥30lbs also had higher mean levels of the IGF-1/IGFBP-3 ratio. Since serum IGF-1 and IGFBP-3 are objective measures that are known to increase rapidly during puberty, the results of our pilot study support that the maternal BMI, GWG and rapid infant weight gain are associated with biological changes in the girls. Our findings suggest that measurement error in outcome assessment or confounding did not drive the associations that we observed between these factors and earlier onset of breast development. In conclusion, we identified higher maternal pre-pregnancy BMI, excess GWG and rapid growth during infancy as modifiable factors associated with earlier onset of breast development in girls across the spectrum of familial risk for breast cancer. While this suggests that modifying these factors may decrease breast cancer risk later in life, further research should consider additional and potentially opposing pathways, such as childhood body size, through which the early-life environment affects breast cancer risk.